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Selexipag for the Treatment of Pulmonary Arterial Hypertension Richard Wells, MD

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Page 1: Selexipag)for)the)Treatmentof) …...Background) • Prostanoids) – Transformed)the)care)of)paents)with)PAH – Epoprostenol))(syntheBc)PGI2))remains)one)of)the) few)PAHtherapies)shown)to)reduce

Selexipag  for  the  Treatment  of  Pulmonary  Arterial  Hypertension  

Richard  Wells,  MD  

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ObjecBves  

•  Prostacyclin  pathway  in  pulmonary  arterial  hypertension  (PAH)  

•  Current  guidelines  for  management  of  PAH  with  prostacyclin  analogues  (prostanoids)  

•  Pharmacology  of  prostanoids  •  Evidenced  based  medicine  for  the  use  of  selexipag  

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Background  •  Prostacyclin  Pathway  

–  Endothelial  cells  use  arachidonic  acid  to  produce  prostacyclin  (PGI2)  

–  Effects  mediated  through  increased  cyclic  AMP  (cAMP)  producBon  

–  Potent  vasodilator  

–  Cyto-­‐protecBve  and  anB-­‐proliferaBve  effects  

–  PAH  paBents  show  reducBon  in  prostacyclin  synthase  expression  and  reducBon  in  metabolites  of  PGI2  

Galiè  N  et  al.    Updated  Treatment  Algorithm  of  Pulmonary  Arterial  Hypertension.    Journal  Am  Col  Card  2013;  62(25  D)  

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Background  

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Pulmonary  Arterial  Hypertension  Treatment  

WSPH  2013    Prostanoids  recommended  for  WHO  group  1  PAH  who  are  NYHA  III  and  IV  

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Background  

•  Prostanoids  – Transformed  the  care  of  paBents  with  PAH  

– Epoprostenol    (syntheBc  PGI2)  remains  one  of  the  few  PAH  therapies  shown  to  reduce  mortality    

Galiè  N  et  al.    Updated  Treatment  Algorithm  of  Pulmonary  Arterial  Hypertension.    Journal  Am  Col  Card  2013;  62(25  D)  

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PAH-­‐Specific  Treatments  

McLaughlin  VV  et  al.    Contemporary  Trends  in  the  Diagnosis  and  Management  of  Pulmonary  Arterial  Hypertension:  An  IniBaBve  to  Close  the  Care  Gap.    Chest  2013;  143(2):  324-­‐332  

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Prostanoids  

•  REVEAL  study  – Demonstrated  that  40%  of  PAH  paBents  who  died  did  not  receive  a  prostanoid  at  the  Bme  of  death  

Farber  HW  et  al.    Use  f  parenteral  prostanoids  at  Bme  of  death  in  paBents  with  pulmonary  arterial  hypertension  in  REVEAL.    Chest  2011;  140:  903A  

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Background  

•  Prostacyclin  therapy  – Side  effects  

•  Headache  •  Nausea  vomiBng  •  Jaw  pain  •  Flushing  •  Diarrhea  •  Hypotension  •  Paresthesia  •  Anxiety  

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Background  •  Prostanoid  

–  RelaBvely  short  in  vivo  half-­‐lives    •  Administered  by  either  conBnuous  intravenous  or  subcutaneous  infusion  

–  Extreme  inconvenience  

–  CRBSI  

–  Intractable  site  pain  in  the  case  subcutaneous  infusion  

–  Other  line  complicaBons  •  Line  falling  out  •  Break  in  tubing  •  Lumen  blockage    

Bourge,  RC  et  al.    Rapid  transiBon  from  inhaled  iloprost  to  inhaled  treprosBnil  in  paBents  with  pulmonary  arterial  hypertension.    Cardiovasc  Ther  2013;  31(1):  38-­‐44  

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Background  

•  Inhaled  prostanoids  – Local  effects  and  fewer  side  effects    – Frequent  dosing  and  inconvenience  

 

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The  Ideal  Prostanoid  •  Longer  half  life  →  Fewer  dosages  

•  Oral  formulaBon  

•  EffecBve    –  Improvement  exercise  tolerance  

–  Improvement  in  hemodynamics  

–  ReducBon  in  morbidity  and  mortality  

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Prostanoid  Pharmacology  

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Prostanoids  

•  Prostanoid  receptors  

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Prostanoid  

•  Prostanoids  have  significant  acBons  at  other  prostacyclin  receptors  which  can  contribute  or  miBgate  their  therapeuBc  acBon  

•  Polymorphisms  in  prostanoid  receptors  has  also  been  reported  and  likely  impacts  variaBons  disease  suscepBbility  and  drug  response  

 Clapp  LH  and  Gurung  R.    The  mechanisBc  basis  of  prostacyclinc  and  its  stable  analogues  in  pulmonary  arterial  hypertension:  role  of  membrane  versus  nuclear  receptors.    Prostaglandins  and  other  lipid  mediators  2015;  120:  56-­‐71    Narumiya,  S  and  Fitzgerald  GA.    GeneBc  and  pharmacological  analysis  of  prostanoid  receptor  funcBon.    J.  Clin  Invest.  2001;  108:  25-­‐30  

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Selexipag  

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Selexipag  •  Oral  PGI2  receptor  agonist  

•  Non-­‐prostanoid  pro-­‐drug  

•  Metabolized  rapidly  to  an  acBve  metabolite  with  high  affinity  for  the  classical  human  “IP  receptor”  

•  Metabolite  has  a  long  plasma  half-­‐life  of  8hrs  

•  Selexipag  nor  its  metabolite  binds  to  other  prostacyclin  receptors  with  significant  affinity  

Clapp,  LH  and  Gurung  R.    The  mechanisBc  basis  of  prostacyclin  and  its  stable  analogues  in  pulmonary  arterial  hypertension:  Role  of  membrane  vs  nuclear  receptors.    Prostaglandine  and  other  Lipid  Mediators  2015;  120:  56-­‐71  

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Selexipag  

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Selexipag  Selexipag  

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Selexipag  

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Selexipag-­‐Phase  2  

•  Proof  of  concept  – MulBcenter  – Double  blind  – Placebo  controlled  – 17  weeks  duraBon  

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Selexipag-­‐Phase  2  

•  Inclusion  – Age  ≥18  yrs  –  Idiopathic  or  familial-­‐,  CTD  related-­‐,  corrected  congenital-­‐,  or  anirexogen  use  related-­‐PAH  

– 12  weeks  of  stable  background  therapy  with        PDE-­‐5i  +/-­‐  ERA  

– Baseline  RHC  showing  PVR  >400dyn·∙s·∙cm-­‐5  and  6MWT  150-­‐500m  

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Selexipag-­‐Phase  2  

•  RandomizaBon  was  3:1  (selexipag:placebo)  •  At  week  17  – Selexipag  

•  42.4%  800µg  BID  •  21.2%  600µg  BID  •  18.2%  400µg  BID  •  12.1%  200µg  BID  

– Placebo  •  90%  800µg  BID  

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Selexipag-­‐Phase  2  

•  Follow  up  – UnBl  week  17  paBents  when  RHC  performed    

•  Primary  Outcome  – Change  in  PVR  at  week  17  expressed  as  a  percentage  of  the  baseline  value  

 

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Selexipag-­‐Phase  2  

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Selexipag-­‐Phase  2  Primary  End  Point  -­‐  Treatment  Effect:  -­‐30.3%  

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Selexipag-­‐Phase  2  

•  DemonstraBon  of  the  hemodynamic  effects  of  selexipag  on  PVR  through  agonism  of  the  IP  receptor  

•  Can  only  postulate  that  this  hemodynamic  improvement  translates  into  long  term  PAH  outcomes  

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Selexipag-­‐Phase  3  

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Selexipag-­‐Phase  3  •  GRIPHON,  (Prostacyclin  (PGI2)  Receptor  agonist  

In  Pulmonary  arterial  HypertensiON)  

•  Randomized  (1:1)  

•  Placebo-­‐controlled  trial  

•  MulBcenter  

•  Double-­‐blind  

•  CollaboraBon  between  steering  commiree  and  Actelion  

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Selexipag-­‐Phase  3  

•  Inclusion  – 18-­‐75  yrs  –  Idiopathic,  Familial,  HIV,  CTD,  Drugs  and  toxins-­‐  and  CHD  with  repaired  shunts  

– RHC  confirmed  PAH  with  PVR  at  least  400  dyn·∙s·∙cm-­‐5  and  6MWD  50-­‐450m  

– 12  weeks  of  stable  medicaBon  regimen  excluding  prostanoids  

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Selexipag-­‐Phase  3  •  Dose  adjustment  phase  –  12  weeks    

Started  with  200µg  BID  of  study  drug  

RandomizaBon  to  selexipag  or  placebo  

Weekly  increases  of  200µg  BID  unBl  unmanageable  PGI2  side  effects  occurred  

Weekly  200µg  BID  increase    

Decrease  by  200µg  BID  –  determined  the  maximum  tolerated  dose  for  the  paBent  

Entered  the  maintenance  phase  (max  dose  of  1600µg  BID)  

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Selexipag-­‐Phase  3  

•  Follow  up  – Baseline,  8  weeks,  16  weeks,  26  weeks,  every  6  months  thereater  unBl  the  end  of  the  trial  

– ConBnued  unBl  a  pre-­‐specified  number  of  primary  end  points  occurred  which  was  defined  as  the  end  of  the  study  

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Selexipag-­‐Phase  3  

•  Primary  Outcome  –  Composite  of  all  cause-­‐death  or  complicaBon  related  to  PAH  •  ComplicaBon  related  to  PAH  included:  

– Worsening  of  PAH  that  caused  hospitalizaBon,  iniBaBon  of  parenterals,  long  term  O2  or  need  for  lung  txp  or  balloon  atrial  septostomy  

–  Disease  progression:  ≥15%  drop  in  6MWD  with  worsening  NYHA  FC  or  need  for  addiBonal  PAH  therapy  

•  Independent  blinded  criBcal  event  commiree  adjudicated  all  events  including  death  

 

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Selexipag-­‐Phase  3  

•  Secondary  Outcomes  –  6MWD  up  to  26  weeks  

– Absence  of  worsening  NYHA  FC  up  to  26  weeks  

–  Time  to  event  analysis  of  death  from  PAH  or  hospitalizaBon  from  PAH  

–  Time  to  event  analysis  of  all  cause  death  over  enBre  study  period  

 

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Selexipag-­‐Phase  3  

•  To  achieve  90%  power  to  detect  HR  of  0.65  determined  that  331  primary  outcome  events  would  have  to  be  observed  →  1150  paBents  needed  

•  For  primary  end  point  analysis  paBents,  who  disconBnued  without  having  a  nonfatal  primary  end  point  were  censored  at  Bme  of  disconBnuaBon  

•  KM  method  to  esBmate  end  points  and  log  rank  test  for  comparison  

•  99%  CI  for  primary  and  most  secondary  end  points  

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Selexipag-­‐Phase  3  

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Selexipag-­‐Phase  3  

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Selexipag-­‐Phase  3  

HR,  0.6;  99%  CI  0.46  to  0.78;  p<0.001  

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Selexipag-­‐Phase  3  Hazard  ra-o  (CI)   p  Value  

Primary  analysis   0.6  (99%,  0.46-­‐0.78)   <0.001  

SensiBvity  analysis  (a)   0.65  (95%,  0.54-­‐0.78)   <0.001  

SensiBvity  analysis  (b)   0.82  (95%,  0.70-­‐0.96)   0.007  

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Selexipag-­‐Phase  3  

Low  200-­‐400  µg  BID  Medium  600-­‐1000  µg  BID  High  1200-­‐1600  µg  BID  

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Selexipag-­‐Phase  3  

Page 42: Selexipag)for)the)Treatmentof) …...Background) • Prostanoids) – Transformed)the)care)of)paents)with)PAH – Epoprostenol))(syntheBc)PGI2))remains)one)of)the) few)PAHtherapies)shown)to)reduce

Selexipag  Phase  3  

Page 43: Selexipag)for)the)Treatmentof) …...Background) • Prostanoids) – Transformed)the)care)of)paents)with)PAH – Epoprostenol))(syntheBc)PGI2))remains)one)of)the) few)PAHtherapies)shown)to)reduce

Selexipag  Phase  3  

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Selexipag-­‐Phase  3  

•  6MWD  –  at  week  26  – Median  loss  of  9m  from  baseline  in  placebo  – Median  gain  of  4m  from  baseline  in  selxipag  – Treatment  effect  of  12m  (99%  CI,  1  to  24,  p  0.003)  

•  NYHA  FC  –  at  week  26  – There  was  no  significant  difference  between  placebo  and  selexipag  in  proporBon  of  paBents  with  no  worsening  funcBonal  class  (74.9%  and  77.8%  respecBvely)  

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Selexipag-­‐Phase  3  

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Selexipag-­‐Phase  3  

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Selexipag-­‐Phase  3  

Selexipag  (n=577)   Oral  trepros-nil  FREEDOM-­‐C  (n=174)  

Oral  trepros-nil  FREEDOM-­‐C2  (n=157)  

Headache   65.2   86   71  

Nausea   33.6   64   46  

Diarrhea   42.4   61   55  

VomiBng   18.1   43   21  

Jaw  Pain   25.7   43   25  

Flushing   12.2   49   35  

Extremity  pain   16.9   31   17  

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Take  Home  Points  

•  Selexipag  is  a  non-­‐prostanoid  agonist  selecBve  for  the  IP  receptor  and  mediates  vasodilaBon  of  pulmonary  vasculature  

•  Selxipag  has  a  longer  half  life  than  other  prostanoids  •  In  PAH  selxipag  led  to  an  improvement  in  PVR  and  limited  complicaBons  related  to  PAH  in  phase  2  and  phase  3  trials  respecBvely  

•  Selexipag  causes  side  effects  similar  to  other  prostanoids  

•  Selexipag  may  have  a  berer  side    effects  profile  than  other  oral  prostanoids  

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Thank  you  


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